This is an application for support for a SCOR in Osteoarthritis at Rush-Presbyterian-St. Luke's Medical Center in Chicago. It represents a continuation and an extension of the current SCOR grant (2-P%)-AR-39239) with closely related projects within an integrated program entitled "Osteoarthritis: A continuum." The overall theme of the projects outlined in this application will continue to be the cell biology and biochemistry of articular cartilage but well now include a major focus on molecular analysis of genes critical biology. The major emphasis of the SCOR is to investigate the potential of cartilage cells to repair the tissue following injury. One novel approach to this aim is to analyze the potential of cells derived form damaged cartilage to develop neo-cartilage in vitro. This approach will address the whether genetic/epigenetic changes of damage to the extracellular matrix alone are responsible for disease progression. If particular target genes are found to be altered, molecular "rescue" approaches will be used to validate their role. The process of chondrocytic chondrolysis induced by fragments of extracellular matrix components will continue as a segment of these investigations. The previous SCOR documented the role of specific matrix receptors in this induction. The current program will detail common intracellular signal transduction events involved. Comparative studies of tissues from human knee and ankle joints have revealed distinct differences in composition and metabolism that may predispose the knee joint to and/or protect the ankle joint from progressive degeneration. Differences between chondrocytes of the superficial layer versus deeper layers have also been documented. The current proposal takes the examination of these chondrocyte populations to the next level namely, documenting differences in gene expression, sensitivity to specific cytokines, and response to static/dynamic loading. Previous work has also identified a protein that is selectively expressed by articular chondrocytes within the superficial layer (superficial zone protein, SZP). From this, an exciting new project is proposed, namely to characterize the promoter region of SZP. The goal is to identify cis-element binding sites within the promoter that regulate SZP transcription at the molecular level as well as the environmental factors (e.g. cytokines) that modulate SZP expression at the cellular level. The clinical research project will evaluate the effects a non-surgical intervention approach designed to reduce medial knee OA pain as well as the adduction moment. A lateral wedged contoured orthotic device will used in human subjects and clinical as well as biochemical (i.e. markers) outcome measures will be collected. The proposed studies will encompass five individual yet overlapping projects supported by two Core Facilities.